Hepatocyte nuclear factors dynamically regulate triglyceride metabolic reprogramming in metabolic dysfunction-associated steatotic liver disease: Mechanisms and implications

Table 2 Role of hepatocyte nuclear factors in triglyceride metabolism in metabolic dysfunction-associated steatotic liver disease

HNF	Model	Target	Mechanism	Main results	Ref.
HNF-1α	C57BL/6J mice	L-FABP↑	Promotes the transport of long-chain fatty acids from the intracellular space to specific organelles	Promotes lipid synthesis	[133]
	C57BL/6J mice	PPAR-γ↓	Reduces synthesis of TGs and Cho	Inhibits lipid synthesis	[126]
	C57BL/6J mice	SREBP-1c↓	Inhibits the expression of its target lipogenesis genes	Inhibits TG synthesis	[130]
	HepG2 cells and Huh7 cells	Sigma receptor 1↓	Decreases intracellular lipid droplet formation rate and lipid storage capacity	Inhibits lipid synthesis	[136]
	C57BL/6J mice	PCSK9↑	Mediates degradation of LDL receptors and increases plasma LDL-C levels	Reduces Cho intake	[142]
	-	CYP7A1↑, BSEP↑, NTCP↑	Promotes the elimination of BAs	Reduces Cho accumulation	[143]
	HepG2 cells	MiR-122↓	Enhances miR-122-inhibited SCAP expression and interferes with SREBP-2 maturation	Reduces lipid synthesis and absorption	[130]
HNF-1β	-	Angiopoietin-like protein 8↑	Inhibits LPL activity	Reduces TG hydrolysis	[147,148]
	3T3-L1 preadipocytes	PPAR-γ↓	Enhances mitochondrial oxidative phosphorylation	Accelerates TG decomposition	[149]
	C57BL/6J mice	GPX1↑	Reduces ROS levels, which in turn reduces the expression of SREBP-1, ACC, and FASN	Indirectly inhibits TG synthesis	[151]
	AML-12 cells	SREBP-1c↓	Inhibits the expression of its target lipogenesis genes	Inhibits lipid synthesis	[146]
FOXA1	HepG2 cells	GPAT1↓, DGAT2↓, MTP↓, ApoB↓	Inhibits the expression of its target genes related to TG synthesis and secretion	Inhibits TG synthesis and secretion	[157]
	HepG2 cells	FABP1↑	Activates its transcription	Promotes intracellular transport of fatty acids	[158]
	HepG2 cells	UCP1↑	Enhances its expression and reduces mitochondrial membrane potential	Reduces lipid storage	[157]
	HepG2 cells	HMGCS2↑	Enhances ketone production	Promotes TG catabolism	[157]
FOXA2	HepG2 cells	hFABP1↑	Activates its transcription	Involved in the transport of long-chain fatty acids	[160]
	-	PGC-1β↑	Activates mitochondrial fatty acid oxidation	Enhances FA metabolism	[166]
FOXA3	C57BL/6J mice	ApoA-1↑	Mediates reverse Cho transport by macrophages	Promotes liver cell steatosis	[173]
HNF-4α	HFD mice	ApoB↓	Reduces secretion of VLDL	Promotes lipid accumulation	[187]
	C57BL/6J mice	ULK1↑	Activates lipophagy	Reduces lipid storage	[199]
	HFD mice	CDKL3↑	Induces phosphorylation of FoxO1	Reduces lipid accumulation	[207]
HNF-6	BDL mice	CYP7A1↓	Reduces Cho-to-BA conversion	Severely impairs Cho clearance	[208]

HNF: Hepatocyte nuclear factor; L-FABP: Liver fatty acid-binding protein; PPAR: Peroxisome proliferator-activated receptor; TG: Triglyceride; Cho: Cholesterol; SREBP-1c: Sterol regulatory element-binding protein-lc; PCSK9: Proprotein convertase subtilisin/kexin type 9; LDL: Low-density lipoprotein; LDL-C: Low-density lipoprotein-cholesterol; CYP7A1: Cholesterol 7α-hydroxylase; BSEP: Bile salt export pump; NTCP: Sodium taurocholate cotransporting polypeptide; SCAP: Sterol regulatory element-binding protein cleavage-activating protein; GPX: Glutathione peroxidase; ROS: Reactive oxygen species; ACC: Acetyl-CoA carboxylase; FASN: Fatty acid synthase; FOXA: Forkhead box A; GPAT1: Glycerol-3-phosphate acyltransferase 1; DGAT2: Diacylglycerol acyltransferase 2; MTP: Microsomal triglyceride transfer protein; ApoB: Apolipoproteins B; FABP1: Fatty acid binding protein 1; UCP1: Uncoupling protein 1; HMGCS2: 3-hydroxy-3-methylglutaryl-CoA synthase 2; hFABP1: Human liver fatty acid-binding protein 1; PGC-1β: Peroxisome proliferator-activated receptor gamma coactivator-1β; FA: Fatty acid; VLDL: Very low-density lipoprotein; HFD: High fat diet; ULK1: Unc-51-like autophagy activating kinase 1; CDKL3: Cyclin-dependent kinase-like 3; FoxO1: Forkhead box protein O1.